Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease

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• 作者：Jonathan M. Schott^a ; ^{j.schott@ucl.ac.uk" class="auth_mail" title="E-mail the corresponding author} ; Sebastian J. Crutch^a ; Minerva M. Carrasquillo^b ; James Uphill^c ; Tim J. Shakespeare^a ; Natalie S. Ryan^a ; Keir X. Yong^a ; Manja Lehmann^a ; Nilufer Ertekin-Taner^b ; ^d ; Neill R. Graff-Radford^d ; Bradley F. Boeve^e ; Melissa E. Murray^b ; Qurat ul Ain Khan^b ; Ronald C. Petersen^e ; Dennis W. Dickson^b ; David S. Knopman^e ; Gil D. Rabinovici^f ; Bruce L. Miller^f ; Aida Suá ; rez Gonzá ; lez^a ; ^g ; Eulogio Gil-Né ; ciga^g ; Julie S. Snowden^h ; Jenny Harris^h ; Stuart M. Pickering-Brown^h ; Eva Louwersheimerⁱ ; Wiesje M. van der Flierⁱ ; Philip Scheltensⁱ ; Yolande A. Pijnenburgⁱ ; Douglas Galasko^j ; ^k ; Marie Sarazin^l ; Bruno Dubois^m ; Eloi Magninⁿ ; Daniela Galimberti^o ; Elio Scarpini^o ; Stefano F. Cappa^p ; John R. Hodges^q ; Glenda M. Halliday^q ; Lauren Bartley^q ; Maria C. Carrillo^r ; Jose T. Bras^s ; John Hardy^s ; Martin N. Rossor^a ; John Collinge^c ; Nick C. Fox^a ; Simon Mead^c
• 关键词：Posterior cortical atrophy ; Alzheimer's disease ; Genetics ; GWAS ; Selective vulnerability ; APOE
• 刊名：Alzheimer's & Dementia
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：12
• 期：8
• 页码：862-871
• 全文大小：1250 K

文摘

The genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain.

Methods

We genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome-wide association study.

Results

We confirm that variation in/near APOE/TOMM40 (P = 6 × 10⁻¹⁴) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10⁻⁴), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome-wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10⁻¹⁰ OR = 1.9 [1.5–2.3]); rs72907046 near FAM46A (P = 1 × 10⁻⁹ OR = 3.2 [2.1–4.9]); and rs2525776 near SEMA3C (P = 1 × 10⁻⁸, OR = 3.3 [2.1–5.1]).

Discussion

We provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD.